Study of Treatment for Pulmonary Hypertension In Sickle Cell Patients Stopped Due to Safety Concerns

*NHLBI Stops Study of Treatment for Pulmonary Hypertension in Patients
with Sickle Cell Disease Due to Safety Concerns *

The National Heart, Lung, and Blood Institute (NHLBI) of the National
Institutes of Health has stopped a clinical trial testing a drug
treatment for pulmonary hypertension in adults with sickle cell disease
nearly one year early due to safety concerns. In an interim review of
safety data from 33 participants who completed 16 weeks of treatment,
researchers found that, compared to participants on placebo (dummy
pill), participants taking sildenafil (Revatio) were significantly more
likely to have serious medical problems. The most common problem was
episodes of severe pain called sickle cell crises, which resulted in
hospitalization. No deaths have been associated with the drug in the
clinical trial.

Known as walk-PHaSST, the study was the first multicenter, randomized
clinical trial to test the safety and effectiveness of sildenafil for
pulmonary hypertension in patients with sickle cell disease, one of the
most common genetic blood disorders in the United States. Pulmonary
hypertension is a debilitating condition of high blood pressure in the
arteries that carry blood to the lungs, which can lead to heart failure
and death. Approximately 30 percent of sickle cell disease patients
develop pulmonary hypertension, and even mild levels of pulmonary
hypertension have been associated with sudden death in people with
sickle cell disease.

"The increase in sickle cell medical problems is concern enough for us
to stop this clinical trial to protect the safety of our participants,"
said NHLBI Director Elizabeth G. Nabel, M.D. “We will continue to look
into the possible causes of these preliminary results. In the meantime,
we encourage patients with sickle cell disease who are taking sildenafil
for pulmonary hypertension to talk with their physicians about the
potential risks and benefits of the medication and what actions they
should consider, including whether to taper off this medication and how
to best manage both sickle cell disease and pulmonary hypertension."

Because the medical problems experienced in walk-PHaSST were
complications specific to sickle cell disease, “The findings of the
walk-PHaSST study should not be applied to other groups of patients with
pulmonary hypertension where the drug has been found to be safe and
effective,” Nabel added.

Researchers are conducting extensive analyses of the study results,
which could contribute to recommendations for treating pulmonary
hypertension in patients with sickle cell disease. They will prepare
reports of their research for publication in peer-reviewed journals.

The NHLBI stopped the study on July 7, 2009, based on the unanimous
recommendations of the Pulmonary Complications of Sickle Cell Disease
Data and Safety Monitoring Board (DSMB), an independent advisory group
that has been monitoring the study since it began. This DSMB is composed
of experts in sickle cell disease, lung disease, statistics, and bioethics.

Participants in walk-PHaSST have discussed the preliminary findings of
the study with their study clinicians. They have been instructed to
taper sildenafil treatment over a period of three to seven days to
minimize problems associated with immediate withdrawal from the drug,
such as worsening of symptoms of pulmonary hypertension. Researchers
will continue to monitor participants and conduct further analyses to
assess the findings.

Walk-PHaSST was designed to determine whether sildenafil lessens the
symptoms of pulmonary hypertension, such as shortness of breath, by
improving heart and lung function, in individuals with sickle cell
disease who develop pulmonary hypertension. The primary outcome measure
was the results of a six-minute walk test, a standard indicator of a
person's heart and lung function. Hence, the name walk-PHaSST reflects
the primary test used to assess effectiveness of the treatment ("walk"
test) for _P_ulmonary _H_ypertension _a_nd _S_ickle Cell Disease with
_S_ildenafil _T_herapy. Researchers also evaluated the safety of the
drug for sickle cell disease patients through reports of adverse effects
and laboratory tests.

Sildenafil is approved by the Food and Drug Administration for use in
patients with pulmonary hypertension. In general, the drug treats
pulmonary hypertension by relaxing the blood vessels in the lungs to
allow blood to flow more easily. Since sildenafil is not FDA-approved to
treat pulmonary hypertension in patients with sickle cell disease, the
walk-PHaSST study was conducted under an investigational new drug
application. The FDA was notified of the termination of the study on
July 14.

Walk-PHaSST began recruiting participants in July 2007 and enrolled 74
patients over the age of 19 (average age 45). Participants had sickle
cell disease and mild to severe pulmonary hypertension. They were
randomly assigned to receive sildenafil or placebo for 16 weeks.
Participants could also receive other therapies as needed to manage
sickle cell and related complications. After completing the study
treatment (or placebo), participants could choose to be part of the
open-label follow-up phase of the study and continue to be assessed for
up to one year. In the open-label study, participants and clinicians
knew that sildenafil was being taken. When the study was stopped, 33
participants had completed the clinical trial.

"Although these preliminary results are disappointing, we expect that
the study's results, once fully analyzed, will provide important
insights into the role of pulmonary hypertension in sickle cell
disease," said Mark Gladwin, M.D., lead investigator of walk-PHaSST and
director of the Vascular Medicine Institute at the University of
Pittsburgh. Gladwin is also a special volunteer for the NHLBI and was
formerly a senior investigator with the Critical Care Medicine
Department at the NIH Clinical Center and chief of the NHLBI Pulmonary
and Vascular Medicine Branch.

The design of the walk-PHaSST study was based on extensive evidence that
sildenafil improves pulmonary hypertension regardless of its cause and
on results of a small, open-label, nonrandomized pilot study led by
Gladwin while he was at the NIH. The pilot study evaluated 12 sickle
cell patients with mild or moderate pulmonary hypertension who were
being treated with sildenafil and with hydroxyurea, a drug known to help
reduce the numbers of episodes of sickle cell pain crises and acute
chest syndrome, as well as hospitalizations and blood transfusions
needed. In 2005, Gladwin and his colleagues reported that after about 6
months, sildenafil was well tolerated, decreased pulmonary blood
pressure, and increased exercise capacity.